Investigational PD-1 inhibitors for advanced non-small lung cancer: new players in a shifting paradigm

KEYWORDS:

• Immunotherapy
• non-small cell lung cancer
• PD-1 inhibitors
• PD-L1 inhibitors
• PDR001
• REGN2810
• MEDI0680
• 244C8
• 388D4

1. Introduction

Immune surveillance is the process by which naive T cells circulate throughout the body searching for aberrant or mutated antigens expressed on tumor cells in order to identify and destroy these cells. An immune response is initiated when a foreign or tumor-specific antigen is presented by the major histocompatibility complex (MHC) on the surface of antigen-presenting cells such as macrophages or dendritic cells and presented to a T cell. In addition to the interaction between MHC and T-cell receptors, the immune response is regulated by costimulatory signals that could either potentiate or inhibit the immune response. Usually, these inhibitory signals are found on normal body cells. Therefore, they are important to prevent autoimmunity and to avoid excess immune destruction of normal tissue in the event where the immune system is fighting an infection. This has earned them the designation of immune checkpoints. Certain tumor cells, however, overexpress these inhibitory signals and manage to avoid immune surveillance and become clinically apparent through the phenomenon of ‘immune escape.’ Recently, researchers have managed to block two of these pathways in advanced non-small-cell lung cancer (NSCLC), therefore removing the ‘brake’ on the immune response. These two pathways include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) coreceptors as well as the programmed cell death-1 (PD-1) antigen which interacts with its ligands, PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273) [1]. The drugs that block these pathways are called immune checkpoint inhibitors. The Keynote-024 trial has changed the approach to advanced NSCLC after showing a superiority for pembrolizumab (PD-1 inhibitor) as first-line therapy compared to platinum-based chemotherapy with regard to overall and progression-free survival in patients with PD-L1 >50% [2]. It has, therefore, become part of the initial workup to test for PD-L1 status in these cases. It is important to note, however, that in the Checkmate-026 trial, nivolumab (PD-1 monoclonal antibody) did not prove to be superior to platinum-based therapy as first-line therapy in advanced NSCLC. Critics attributed this negative result to be due to an inferiority of nivolumab compared to pembrolizumab with regard to PD-1 inhibition, the use of a lower threshold of PD-L1 of 5% compared to 50% in the Keynote-024, or a difference in patient population with a higher proportion of nonsmokers and inclusion of untreated patients with brain metastases in the Checkmate-026 trial [3]. Nivolumab has, however, shown to be superior to docetaxel in second-line therapy of advanced non-squamous NSCLC for which it earned its FDA approval. It was the first immune checkpoint inhibitor to gain approval for advanced NSCLC [4]. In this editorial, we will be looking at the PD-1 inhibitors currently being investigated in the pipeline from preclinical to phase II studies for the treatment of NSCLC.

2. Novel PD-1 inhibitors

2.1. 244C8 and 388D4

Scheuplein et al. studied the in vivo efficacy of two novel humanized anti-PD-1 antibodies 244C8 and 388D4 in patient-derived tumor xenografts derived from a core needle biopsy of a patient with metastatic NSCLC. These xenografts were implanted into immune-humanized NSG mice. 244C8 represents a novel class of anti-PD-1 antibodies seeing as it does not to compete with currently marketed antibodies for PD-1 (nivolumab or pembrolizumab) nor does it compete with PD-L1 for PD-1 binding. However, antibodies from the 244C8 family elicit both a higher T-cell activation and an increased expression of the high-affinity interleukin-2 receptor CD25 than currently marketed anti-PD-1 antibodies in ex vivo human cell-based assays. This suggests a different mechanism of action for 244C8. Both 244C8 and 388D4 were compared to pembrolizumab and showed similar efficacy in tumor growth inhibition (TGi) at 28 days. The TGi of 244C8 and 388D4 were 40% and 38%, respectively, compared to 37% for pembrolizumab, and this was a statistically significant difference relative to vehicle, with Student t-test p values <0.003 at end of study assessment. These results show that, contrary to expectation, competition for binding to PD-L1 ligand by an anti-PD-1 antibody may not be a prerequisite for functional efficacy, as 244C8 does not have this property but was active [5].

2.2. PDR001

PDR001 is a humanized anti-PD-1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1 that has been studied in a recent phase I study by Naing et al. with patients having advanced solid tumors. According to preliminary data, PDR001 was well tolerated and had a similar toxicity profile to currently marketed PD-1 inhibitors. Three cases of hypothyroidism were suspected to be related to PDR001 and were reported. A single case of grade 3 autoimmune colitis was the only serious adverse event suspected to be related to PDR001. The recommended phase II dosing was determined and a phase II study is currently underway [6]. Another phase I study is underway studying antitumor activity of FAZ053 (a novel anti-PD-L1) as a single agent or in combination with PDR001 in adult patients with advanced solid tumors [7].

REGN2810 is another PD-1 inhibitor, fully human hinge-stabilized IgG4, currently under investigation. The most important is a phase I, open-label, multicenter, ascending-dose-escalation study of REGN2810, alone and in combination with other anticancer therapies such as chemotherapy and hypofractionated radiation therapy (hfRT) in patients with advanced malignancies. Preliminary data show that REGN2810 is so far well tolerated. Drug-related adverse events of grade 3 or higher were transaminase elevation (n = 2), anemia (n = 1), and anti-Hu-associated paraneoplastic encephalitis (n = 1) out of a total of 58 patients at the time of analysis. There were no drug-limiting toxicities, and responses appear augmented when hfRT is added to REGN2810, suggesting abscopal effects. Multiple expansion cohorts are evaluating REGN2810 at the recommended dose of 3 mg/kg q 2 weeks combined with hfRT and other antitumor regimens [8]. Starting in June 2017, a phase III study was launched comparing platinum-based chemotherapies to REGN2810 in patients with metastatic NSCLC [9].

2.3. MEDI0680

MEDI0680 is a humanized IgG4κ monoclonal antibody specific for human PD-1 that blocks binding of both PD-L1 and PD-L2. It was supposed that blockage of both ligands will lead to a broader tumor response. In addition, Hamid et al. wanted to study the effects of combining MEDI0680 with a PD-L1 inhibitor, durvalumab. Therefore, they are conducting a phase I/II, open-label study to evaluate the safety and antitumor activity of MEDI0680 (AMP-514) in combination with durvalumab versus nivolumab monotherapy in subjects with select advanced malignancies [10]. Preliminary data are still unavailable.

3. Expert opinion

The ultimate question lies in why do we need new investigational drugs that work on PD-1 blockade. While PD-1/PD-L1 inhibitors have proven their effectiveness in treating melanoma, it has been shown that as many as 60% of patients who receive it display primary resistance [11]. What is more worrying is that in melanoma patients who are initially responsive to PD-1 blockade, 25% seem to acquire resistance and have progression after a median follow-up of 21 months [12]. Several authors have attempted to understand the mechanism underlying this acquired resistance, but it remains unclear [13]. It is also unclear whether acquired resistance will develop in other types of tumors treated with PD-1/PD-L1 blockade seeing as the mutagenic potential of tumors is different. Therefore, newly investigated PD-1 inhibitors could be useful in overcoming primary resistance by having different targets such as in the case of PDR001 that blocks the binding of both PD-L1 and PD-L2 [7]. Head-to-head comparisons between the different PD-1 inhibitors, however, should be done to evaluate the affinity of each inhibitor to PD-1 as well as their capacity to block both PD-L1 and PD-L2 binding. Another strategy that could be undertaken is by using combination blockade of both PD-1 and PD-L1 such as in the trial looking at MEDIO0680 in combination with durvalumab versus nivolumab monotherapy [10]. Finally, another possibility that could be investigated is whether any of these new PD-1 inhibitors could play a role as second-line immunotherapy. On another note, Lee et al. have attempted to improve the development of monoclonal antibodies by looking at the crystal structures of nivolumab and pembrolizumab when bound to PD-1, therefore elucidating the specific epitopes implicated [14]. For immunotherapy to be efficient, there are two underlying conditions that are supposed to be fulfilled in the immune environment of the tumor. There should be an endogenous antitumor immune response reflected by T cells present in the peritumoral area blocked by an upregulation of PD-L1 expression on tumor cells. Immune checkpoint inhibitors only address the blockage of the immune response. Future studies are looking at methods of enhancing the antitumor immune response whether with chemotherapy or radiation therapy in addition to the use of immune checkpoint inhibitors in order to achieve an increased and more durable response. Preliminary data are supportive of combination therapies as previously reported, for example, with REGN2810 and hfRT [8]. Hopefully, the following years will provide us with enough data from all the ongoing studies to support the use of novel PD-1 inhibitors in addition to their placement within a treatment algorithm dedicated towards patients with advanced NSCLC.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.