Beyond platinum treatment for NSCLC: what does the future hold?

KEYWORDS:

• Non-small cell lung cancer (NSCLC)
• immunotherapy
• immune checkpoint blockade
• nivolumab
• pembrolizumab

Cytotoxic chemotherapy is a suboptimal therapeutic ‘one-size fits all’ approach for metastatic non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor, modestly improves the overall survival (OS) of lung adenocarcinoma patients in combination with first-line chemotherapy [1,2]. Nintedanib, a triple tyrosine kinase inhibitor (TKI), which blocks vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, in combination with docetaxel improved progression-free survival (PFS) of metastatic lung adenocarcinoma after first-line chemotherapy [3]. The antiepidermal growth factor receptor (EGFR) monoclonal antibody, necitumumab, has been approved in combination with gemcitabine and cisplatin as a first-line treatment of squamous NSCLC based on a 16% decrease of risk of death with the combination compared to chemotherapy alone [4]. However, the lack of validated predictive biomarkers remains an issue for both antiangiogenic drugs and anti-EGFR monoclonal antibodies. Major advances in lung cancer treatment have been made after the discovery of actionable oncogenic alterations in small subsets of NSCLC, including EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements that confer sensitivity to EGFR and ALK TKIs [5,6]. The introduction of oncogene-directed therapies has also affected the diagnostic approach of NSCLC patients, since molecular testing has been rapidly incorporated into clinical routine for guiding treatment decisions. Still there are two important caveats in the field of targeted therapies for NSCLC. The first is the fact that patients with targetable genomic alterations represent a relatively small percentage of the total NSCLC population, mainly adenocarcinoma. The second is that the long-term benefit from molecularly targeted agents is limited by acquired resistance, which is inevitably developed in oncogene-addicted cells under chronic drug exposure through different molecular mechanisms [7].

Alternative therapeutic approaches have been advocated to obtain a long-lasting disease control and improve survival of NSCLC patients, independently of the histology or the presence of genetic alterations. Immunotherapy has gained a renewed interest across a variety of different solid malignancies, including those traditionally considered nonimmunogenic, such as NSCLC. Immune checkpoint blockade (ICB) has demonstrated great promise in NSCLC as well as a variety of malignancies [8]. The immune checkpoints include the programmed cell death protein 1 (PD-1) with its ligand (PD-L1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, which are designated to modulate antigen-specific T-cell responses in order to maintain self-tolerance and limit collateral peripheral tissues damage under physiological conditions [9]. These inhibitory pathways are frequently activated and exploited by tumors to escape from immune surveillance and maintain an immunosuppressive tumor microenvironment. Therefore, monoclonal antibodies against CTLA-4, PD-1, and PD-L1 reverse cancer immunosuppression and enhance antitumor immunity. In early phase I and II studies, PD-1/PD-L1 inhibitors have shown significant antitumor activity with durable clinical responses and a manageable toxicity profile in pretreated patients with multiple, advanced cancer types, including NSCLC (reviewed in ref [8]). In March 2015, the first approval for a checkpoint inhibitor came for the anti-PD-1 monoclonal antibody nivolumab, after the positive results of the phase III CheckMate 017 study, showing a significant, almost 3-month, survival improvement with nivolumab compared to docetaxel as second-line therapy for advanced, squamous NSCLC patients [10]. The same year, the US FDA expanded the indication of nivolumab to include nonsquamous, pretreated NSCLC after the results of the phase III CheckMate 057 study in which nivolumab increased survival compared to docetaxel [11]. In both studies, nivolumab was associated with a better safety profile compared to chemotherapy. A correlation between nivolumab benefit and tumor PD-L1 expression was found for nonsquamous NSCLC patients [11]. Pembrolizumab, another PD-1 inhibitor, has shown superior efficacy compared to docetaxel in previously treated PD-L1-positive NSCLC patients [12]. Indeed, a good predictive role of PD-L1 expression has been demonstrated in all reported trials of pembrolizumab, which is FDA approved as second-line therapy for patients with metastatic NSCLC whose tumors express PD-L1 (tumor proportion score (TPS) ≥1%). In addition, FDA has approved the PD-L1 IHC 22C3 pharmDx, as a companion diagnostic test for PD-L1 testing in NSCLC [13].

Based on the role of ICB in the second-line setting of advanced NSCLC, several studies have been conducted to test immunotherapy as a first-line therapeutic approach. Nivolumab monotherapy demonstrated activity and good tolerance in the phase I CheckMate 012 trial [14]. Response rates were higher in patients with tumor PD-L1 expression with a trend for better activity as the PD-L1 expression levels increased. Activity was also observed in patients with lower or no PD-L1 expression [14]. In the expansion cohort G of the phase II KEYNOTE-021 study, the addition of pembrolizumab to first-line platinum-based chemotherapy demonstrated an overall response rate of 80% for patients with PD-L1 on ≥50% of tumor cells [15]. PFS was also significantly improved with pembrolizumab in comparison to chemotherapy alone (HR 0.53, p = 0.01) [15]. In the phase III KEYNOTE-024, untreated patients with advanced NSCLC and high PD-L1 expression (defined as expression in at least 50% of tumor cells) received either pembrolizumab or platinum-based chemotherapy [16]. Median PFS was significantly longer with pembrolizumab compared to chemotherapy (10.3 months versus 6.0 months). All the efficacy endpoints (OS at 6 months, response rate, and duration of response), as well as tolerability, were in favor of pembrolizumab [16]. Based on this study, pembrolizumab is now FDA approved for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (TPS≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [16]. In contrast, when nivolumab was compared with first-line platinum-based chemotherapy in NSCLC patients with PD-L1 expression on ≥1% tumor cells (CheckMate 026), the results in patients with ≥5% were negative in terms of both PFS and OS [17]. These results indicate that PD-L1 expression is not currently able to define the patients more likely to derive benefit from nivolumab. Indeed, the predictive role of PD-L1 expression should be critically assessed taking into account several factors, including the different immunohistochemistry assays with various cutoff values to define PD-L1 positivity in the ICB studies, as well as the heterogenous tumor PD-L1 expression. In addition, responses to ICB have also been observed among PD-L1-negative patients, underscoring the need for identification and validation of other, beyond PD-L1, biomarkers of response to ICB. Some clinical and biological parameters that may influence the efficacy of ICB have been already identified, such as smoking status, tumor mutational load, and preexisting CD8 + T-cell infiltration [8].

The understanding of the dual functions of interferon-related signaling on the immune system and its nonimmune effects can also unravel the diverse responses to ICB [18]. During virus infection, virus-derived nucleic acids are mainly sensed by certain pattern-recognition receptors (PRRs), such as retinoic acid-inducible gene 1 (RIG1). Binding of RIG1 to its ligand RNAs or short double-stranded RNAs activates the signaling pathways dependent on the adaptor protein mitochondrial antiviral signaling proteins, leading to induction of the interferon (IFN)-regulatory factor-3 (IRF-3) and nuclear factor-κB-dependent gene expression and the subsequent production of type-I and type-II IFNs and inflammatory cytokines [19,20]. Chemotherapy and radiotherapy activate PRRs, which are critical for INF-I production, priming of T cells and enhancement of ICB [18]. Tumor material can act as damage-associated molecular patterns that are engaged on dendritic cells and/or tumor-associated macrophages to finally augment IFN-I production and contribute to immune-mediated regression of irradiated or chemotherapy-treated tumors [18]. However, when INF-I signaling persists, it switches from immune stimulatory to immune suppressive. Persistent INFβ promotes expression of suppressive factors, such as PD-L1. On the other hand, elevated expression of PRRs and INF-stimulated genes also has immune-independent effects and, through stromal fibroblasts and cell exosomes, leads to chemotherapy resistance [18]. Despite negative results from the CheckMate 026 study, alternative therapeutic strategies, including nivolumab in combination with other immunotherapeutic agents, might be able to improve its clinical efficacy as a single agent. Interestingly, the ongoing phase III CheckMate 227 trial aims to evaluate nivolumab or nivolumab plus ipilimumab versus standard platinum-based chemotherapy in the first-line setting of NSCLC.

Despite the widely established efficacy of immune checkpoint inhibitors in the metastatic setting, their role in the treatment of locally advanced- or early stage-NSCLC needs to be further explored. The standard of care for locally advanced NSCLC is a multidisciplinary therapeutic approach, mainly based on the association of platinum-based chemotherapy and radiotherapy. There is a strong scientific rationale for integrating ICB to these treatment modalities, because both radiation therapy and chemotherapy have shown immunogenic properties. Radiation therapy can induce the release of tumor-associated antigens and stress-related signals that prime and activates T cells to promote tumor regression and this effect may be further enhanced by ICB. Preclinical and clinical observations support a synergistic activity between radiotherapy and immune checkpoint inhibitors [8,21,22]. Ongoing clinical studies are currently testing the combination of immune checkpoint inhibitors to radiotherapy or the use of immune checkpoint inhibitors as sequential therapy after concurrent chemoradiation in NSCLC, including a phase III trial (NCT02125461) of the anti-PD-L1 inhibitor durvalumab (MEDI4736) versus placebo after concurrent chemoradiation in stage III unresectable NSCLC. Efficacy and toxicity results from these trials are highly expected.

Although the selection of NSCLC patients for ICB as monotherapy, or in combination with chemotherapy, radiotherapy, or targeted therapies remains critical, immunotherapy has changed the treatment paradigm of 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 article was not funded.